Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells.

Substitutions in thiophene structure give rise to new derivatives with different biological and pharmacological activities. The present study investigated the cytotoxicity activity of some thiophene derivatives in breast cancer cells maintained in two-dimensional (2D) or in three-dimensional (3D) culture and evaluated the anticancer mechanism of these compounds. Cytotoxicity assays were performed against untransformed cells and against breast cancer cell MCF-7. Apoptosis analysis and in-vitro migration assay were also performed to evaluate the mechanism of induction of cell death. All thiophene derivatives reduced the cell viability in breast cancer cells, showing cytotoxic activity (IC50<30 µmol/l), and SB-200 compound showed the best selectivity index in MCF-7 cells compared with doxorubicin in 2D culture. All thiophene derivatives significantly induced G0/G1 phase cell cycle arrest. However, only SB-83 treatment was effective against motility of MCF-7 cells in 2D culture (P=0.0059). The SB-200 derivative treatment induced an increased proportion of acridine orange/Hoechst double-stained cells (35.35 vs. 3.14%, P=0.0002) compared with nontreated cells, with apoptosis morphological alterations independent of caspase 7 activation (P>0.05). MCF-7 cells became less responsive to SB-200 and to doxorubicin in 3D culture compared with cells in 2D culture (higher IC50 values); however, SB-200 showed a better cytotoxic effect compared with doxorubicin in 3D culture. Therefore, the current study provides an insight into anticancer potential of thiophene derivatives, and further studies should be conducted to understand the mechanism by which thiophene derivatives act on cancer cells.

In vivo study of schistosomicidal action of 1-benzyl-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one.

Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.

2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro.

This study evaluated the effects of 2-amino-thiophene derivatives on the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and their possible mechanisms of action. Initially, we evaluated the antileishmanial activity of ten 2-amino-thiophene derivatives on promastigote and axenic amastigote forms of Leishmania amazonensis and their cytotoxicity against murine macrophages and human red blood cells. Three promising compounds were selected for studies of the cell death process using flow cytometry analysis and a DNA fragmentation assay. The effects of the compounds were assessed on intramacrophagic amastigotes, and the modulation of cytokine and NO production was investigated. All thiophene derivatives showed antileishmanial activity against promastigotes and axenic amastigotes with less toxicity for murine macrophages and human red blood cells. The best values were obtained for compounds containing a lateral indole ring. Docking studies suggested that these compounds played an important role in inhibiting trypanothione reductase (TryR) activity. The selected compounds SB-200, SB-44, and SB-83 induced apoptosis in promastigotes involving phosphatidylserine externalization and DNA fragmentation in a pattern similar to that observed for the positive control. Additionally, SB-200, SB-44, and SB-83 significantly reduced the infection index of macrophages by the parasites; for compounds SB-200 and SB-83 this reduction was associated with increased TNF-α, IL-12, and NO levels. This study demonstrated the effective and selective action of 2-amino-thiophene derivatives against L. amazonensis, resulting in apoptosis-like cell death and immunomodulation in vitro. The results suggest that they are promising compounds for the development of new leishmanicidal drugs.

Synthesis, DNA Binding, and Antiproliferative Activity of Novel Acridine-Thiosemicarbazone Derivatives.

In this work, the acridine nucleus was used as a lead-compound for structural modification by adding different substituted thiosemicarbazide moieties. Eight new (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide derivatives (3a-h) were synthesized, their antiproliferative activities were evaluated, and DNA binding properties were performed with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated by addition of ctDNA to the derivatives. The calculated binding constants ranged from 1.74 × 10(4) to 1.0 × 10(6) M(-1) and quenching constants from -0.2 × 10(4) to 2.18 × 10(4) M(-1) indicating high affinity to ctDNA base pairs. The most efficient compound in binding to ctDNA in vitro was (Z)-2-(acridin-9-ylmethylene)-N- (4-chlorophenyl) hydrazinecarbothioamide (3f), while the most active compound in antiproliferative assay was (Z)-2-(acridin-9-ylmethylene)-N-phenylhydrazinecarbothioamide (3a). There was no correlation between DNA-binding and in vitro antiproliferative activity, but the results suggest that DNA binding can be involved in the biological activity mechanism. This study may guide the choice of the size and shape of the intercalating part of the ligand and the strategic selection of substituents that increase DNA-binding or antiproliferative properties.

Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands.

Eight new 5-arylidene-3-benzyl-thiazolidine-2,4-diones with halide groups on their benzyl rings were synthesized and assayed in vivo to investigate their anti-inflammatory activities. These compounds showed considerable biological efficacy when compared to rosiglitazone, a potent and well-known agonist of PPARgamma, which was used as a reference drug. This suggests that the substituted 5-arylidene and 3-benzylidene groups play important roles in the anti-inflammatory properties of this class of compounds. Docking studies with these compounds indicated that they exhibit specific interactions with key residues located in the site of the PPARgamma structure, which corroborates the hypothesis that these molecules are potential ligands of PPARgamma. In addition, competition binding assays showed that four of these compounds bound directly to the ligand-binding domain of PPARgamma, with reduced affinity when compared to rosiglitazone. An important trend was observed between the docking scores and the anti-inflammatory activities of this set of molecules. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromo-benzyl)-5-(4-methanesulfonyl-benzylidene)-thiazolidine-2,4-dione compound had the best activity and the best docking score. Almost all of the stronger hydrophilic interactions occurred between the substituted 5-arylidene group of this compound and the residues of the binding site.